Regulation of the telomerase
by Jan-Philipp Lamping
Date of Examination:2025-08-21
Date of issue:2025-12-16
Advisor:Prof. Dr. Heike Krebber
Referee:Prof. Dr. Heike Krebber
Referee:Prof. Dr. Jörg Großhans
Persistent Address:
http://dx.doi.org/10.53846/goediss-11701
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Abstract
English
Transcription is essential to transfer genetic information and to allow cell viability. Cells must control the resulting traffic of RNA polymerases (RNAP) by holding transcription into gene boundaries and prevent conflicts with other RNA or DNA polymerases, which threaten genome stability. Neverthe-less, transcription termination of RNAPII turns out to be not efficient but rather allows transcription termination and 3’ end processing at multiple sites at terminator regions. So called, alternative poly-adenylation gives rise to different same gene 3’ isoforms with different 3’ untranslated region (3’UTR) length. On the one hand, this imposes regulative potential as the length of 3’UTRs affects half-life, localization, folding and translational value of an mRNA. One the other hand, it increases the risk of polymerase conflicts. Modulators of alternative polyadenylation were heavily investigated as altera-tion can result in various diseases including cancer. However, the complex interplay of multiple fac-tors and complexes remains to be decrypted. In this study we found an interplay between components of the two main transcription termination pathways in S. cerevisiae: mediated by the cleavage and polyadenylation and cleavage factor com-plex (CPF-CF) or the Nrd1-Nab3-Sen1 complex (NNS). We revealed that the scaffold RNA of the telomerase, TLC1, is terminated by the CPF-CF complex, however, is supported by Nrd1 and Nab3 binding at the terminator region, which serves a so far unknown function in NP-braking. Binding of Nrd1 and Nab3 upstream of the poly(A)-signal (PAS) slows transcription of RNAPII and, thereby, allows efficient formation of the CPF-CF complex at one specific PAS. This results in predominant presence of one 3’ isoform and efficient release of RNAPII from the DNA. In addition, the binding of Nrd1 and Nab3 serves as a guard-like quality control factor. CPF-CF formation on proximal sites releases both factors, however, if CPF-CF formation failed at these sites and occurs downstream, Nrd1 and Nab3 remain bound and mediate decay of these readthrough transcripts. Strikingly, we found that NP-braking is a more general mechanism for CPF-CF-mediated transcription termination, being present for ~25 % of mRNAs. NP-braking acts on genes with high risk of polymerase conflicts. In addition, it can result in preferential usage of the downstream PAS site and, thereby, can influence the 3’UTR length and the transcript fate. NP-braking might be a mechanism to ensure genome sta-bility by avoiding polymerase conflicts genome wide and might possess regulative potential under-lining its relevance in transcription termination.
Keywords: Telomerase; Transcription; Transcription termination; CPF-CF; Alternative polyadenylation; NNS; RNA folding; Telomere; ncRNA; lncRNA
